S100A8/A9 Stimulates Keratinocyte Proliferation in the Development of Squamous Cell Carcinoma of the Skin via the Receptor for Advanced Glycation-End Products

Abstract

Squamous cell carcinoma (SCC) is the most common neoplasm in organ transplant recipients (OTR) on long-term immunosuppression and occurs 60- to 100-fold more frequently than in the general population. Here, we present the receptor for advanced glycation end products (RAGE) and S100A8/A9 as important factors driving normal and tumor keratinocyte proliferation. RAGE and S100A8/A9 were transcriptionally upregulated in SCC compared to normal epidermis, as well as in OTR compared to immunocompetent patients (IC) with SCC. The proliferation of normal and SCC keratinocytes was induced by exposure to exogenous S100A8/A9 which in turn was abolished by blocking of RAGE. The migratory activities of normal and SCC keratinocytes were also increased upon exposure to S100A8/A9. We demonstrated that exogenous S100A8/A9 induces phosphorylation of p38 and SAPK/JNK followed by activation of ERK1/2. We hypothesize that RAGE and S100A8/A9 contribute to the development of human SCC by modulating keratinocyte growth and migration. These processes do not seem to be impaired by profound drug-mediated immunosuppression in OTR.

Clinical Implications of High-mobility Group Box-1 (HMGB1) and the Receptor for Advanced Glycation End-products (RAGE) in Cutaneous Malignancy: A Systematic Review

“…RAGE expression was also elevated in organ transplant recipients on long-term immunosuppression when compared to immunocompetent individuals (31).…”

“…Full-text review eliminated six studies due to inappropriate data (use of non-human samples, cell culture only, or animal models) or topic irrelevance to the present review. Ultimately, nine articles were included in this review (25,26,21,(27)(28)(29)(30)(31)(32). The majority of the included studies investigated the role of HMGB1 or RAGE in frozen or formalin-fixed paraffin-embedded (FFPE) tissue from patients with melanoma (25,26,28,29,32).…”

“…Two studies (30, 31) used serum from patients with melanoma, and another study (21) used a cDNA array of melanoma cases. Two studies (27,31) assessed tissue from patients with BCC or cutaneous SCC. Characteristics of each study are summarized in Table I.…”

Chronic Inflammatory Microenvironment in Epidermodysplasia Verruciformis Skin Lesions: Role of the Synergism Between HPV8 E2 and C/EBPβ to Induce Pro-Inflammatory S100A8/A9 Proteins

“…Our study strongly indicates that the cutaneous β-HPV type 8 can actively trigger inflammation, a hallmark of cancer ( Hanahan and Weinberg, 2011 ). In human organ transplant recipients as well as in mouse models of skin carcinogenesis, this involves the induction of the alarmins S100A8/A9 promoting a pro-tumorigenic inflammatory microenvironment ( Gebhardt et al, 2008 ; Iotzova-Weiss et al, 2015 ). S100A8/A9 proteins gained a unique interest over the last decades with respect to their role in cancer progression since they can propel cancer cell proliferation, migration, and invasion ( Bresnick et al, 2015 ).…”

In�vitro anticancer effects of a RAGE inhibitor discovered using a structure-based drug design system

“…RAGE ligands include S100/calgranulins (S100A4, S100A6, S100A7, S100A8/9, S100A14, S100B and S100P) (2,(25)(26)(27)(28)(29) and HMGB-1 protein, which have been demonstrated to be upregulated in glioma, melanoma, bladder, liver, pancreatic, prostate, colorectal, gastric and lung cancer (30)(31)(32)(33)(34). Ligand-RAGE signaling pathways enhance the properties associated with malignant tumor phenotypes (10,22,(35)(36)(37), including by activating members of the small GTPase family (Cdc42 and Rac1), members of the mitogen-activated protein kinase family (extracellular signal-regulated kinase, p38 and stress-activated protein kinases/c-Jun amino-terminal kinases), NF-κB and the formin homology 1 domain (10,22,35-37). Therefore, blocking RAGE and ligand-RAGE signaling could represent a potential strategy for treating certain types of cancer.…”